Arrhythmias In Women Research Articles

Prospective evaluation of corrected QT intervals and arrhythmias after exposure to epirubicin, cyclophosphamide, and 5-fluorouracil in women with breast cancer

Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.

Gene-specific paradoxical QT responses during rapid eye movement sleep in women with congenital long QT syndrome

Patients with congenital long QT syndrome (LQTS) type 2 (LQT2) may develop arrhythmias during emotional stress, acoustic stimuli, or sleep. Women with LQT2 are more susceptible to fatal arrhythmias than are men. The purpose of this study was to examine the effects of sleep on RR and QT intervals in patients with LQT1, in those with LQT2, and in controls and to test the hypothesis that there is a gene-specific effect of sleep on the QT interval in LQT2 that may be especially evident in women with LQT2. Thirty-four subjects with genotyped LQTS and 18 healthy controls were studied. Among the 34 subjects with LQTS, 16 (10 women, age 32 +/- 3 years) had LQT1 and 18 (11 women, age 38 +/- 3 years) had LQT2. Subjects underwent standard polysomnography including ECG recordings. RR, QT, and QTc (Bazett and Fridericia formulas) were measured over recordings obtained during stable conditions during wakefulness, during stage 2 and stages 3-4 of non-rapid eye movement (NREM), and during rapid eye movement (REM) sleep. LQT2 women showed a marked RR decrease and marked QT and QTc increase from NREM to REM sleep, changes that were not observed in either women or men with LQT1 or in men with LQT2. Pronounced cardiac activation during REM and substantial QTc prolongation is noted in a sex- and gene-specific fashion among women with LQT2. REM-related changes in cardiac activation and ventricular repolarization may be implicated in sleep-related malignant arrhythmias in women with the LQT2 genotype.

ОсОбеннОсти диагнОстики и Лечения дисрегу Лят Орных аритмий у женщин в пОстменОпаузе

ОсОбеннОсти диагнОстики и Лечения дисрегу Лят Орных аритмий у женщин в пОстменОпаузе

Effects Of Estrogen On The IKr Channel And Cardiac Repolarization

Females gender itself is a risk factor for drug-induced torsades de pointes (TdP) arrhythmia which is associated with QT prolongation caused by blockade of human ether-a-go-go related gene (hERG) currents. Some clinical evidence suggests that estrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QTC intervals. Although the chronic effects of estrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through estrogen receptors. We here found that the most bioactive estrogen, 17beta-estradiol (E2), acutely delayed cardiac repolarization within the physiological serum level (0.1-1 nM). E2 slightly but significantly suppressed hERG currents (Kd = 0.6 nM) by modifying channel gating kinetics. Mutagenesis study showed the interaction of E2 with F656, a common drug-binding site at the inner pore-cavity of hERG. E2 enhanced both hERG suppression and QTC prolongation by its blocker, E4031. The lack of effects of testosterone on hERG currents and E4031-sensitivity implicates the critical role of aromatic centroid present in E2 but not in testosterone, which is supported by data from aromatase-null mice that cannot produce estrogen. The aromatase-null mice showed lower sensitivity to E4031-induced QT prolongation compared with those of wild type mice, and i.v. application of exogenous E2 (0.1 μg/kg) subsequent to E4031 administration rapidly prolonged QT intervals, indicating that aromatized estrogen emphasize the effect of E4031 on cardiac repolarization in vivo. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QTC prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women.

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effects of Female Hormones on Cardiac Ion Channels and Cardiac Repolarization

Regulation of cardiac ion channels by sex hormones accounts for gender differences in susceptibility to arrhythmias associated with QT prolongation (TdP). Women are more prone to develop TdP than men with either congenital or acquired long-QT syndrome. The risk of drug-induced TdP varies during the menstrual cycle, suggesting that dynamic changes in levels of ovarian steroids, estradiol and progesterone, have cyclical effects on cardiac repolarization. Although increasing evidence suggests that the mechanism of this involves effects of female hormones on cardiac repolarization, it has not been completely clarified. In addition to well-characterized transcriptional regulation of cardiac ion channels and their modifiers through nuclear hormone receptors, we recently reported that physiological levels of female hormones modify functions of cardiac ion channels in mammalian hearts. In this review, we introduce our recent findings showing that physiological levels of the two ovarian steroids have opposite effects on cardiac repolarization. These findings may explain the dynamic changes in risk of arrhythmia in women during the menstrual cycle and around delivery, and they provide clues to avoiding potentially lethal arrhythmias associated with QT prolongation.

Acute effects of oestrogen on the guinea pig and human IKr channels and drug‐induced prolongation of cardiac repolarization

Female gender is a risk factor for drug-induced arrhythmias associated with QT prolongation, which results mostly from blockade of the human ether-a-go-go-related gene (hERG) channel. Some clinical evidence suggests that oestrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QT(C) intervals. Although the chronic effects of oestrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through oestrogen receptors. We therefore investigated acute effects of the most bioactive oestrogen, 17beta-oestradiol (E2) at its physiological concentrations on cardiac repolarization and drug-sensitivity of the hERG (I(Kr)) channel in Langendorff-perfused guinea pig hearts, patch-clamped guinea pig cardiomyocytes and culture cells over-expressing hERG. We found that physiological concentrations of E2 partially suppressed I(Kr) in a receptor-independent manner. E2-induced modification of voltage-dependence causes partial suppression of hERG currents. Mutagenesis studies showed that a common drug-binding residue at the inner pore cavity was critical for the effects of E2 on the hERG channel. Furthermore, E2 enhanced both hERG suppression and QT(C) prolongation by its blocker, E4031. The lack of effects of testosterone at its physiological concentrations on both of hERG currents and E4031-sensitivity of the hERG channel implicates the critical role of aromatic centroid present in E2 but not in testosterone. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QT(C) prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women.

Implantable Cardioverter-Defibrillator Use and Benefit in Women

Women currently receive far fewer implantable cardioverter-defibrillators (ICDs) than do men. Some studies suggest bias in device utilization, with fewer women receiving ICDs despite a similar clinical profile. Other studies, however, describe differences in clinical presentation and arrhythmia risk. There may be autonomic and electrophysiological factors that suggest a lower susceptibility to arrhythmia in women. Although the data on the benefits of the ICD in women are limited by the low numbers of women enrolled in the landmark studies, most studies do suggest an efficacy in women similar to that in men. Further research is needed on the use of ICDs in women.

Arrhythmia and reduced heart rate variability during pregnancy in women with congenital heart disease and previous reparative surgery

Objectives Tachyarrhythmia during pregnancy may have an adverse effect on the mother and the fetus. Heart rate variability (HRV) is a significant marker of autonomic nervous function and may predict tachyarrhythmia. HRV and incidence of arrhythmia in women with repaired congenital heart disease (CHD) during pregnancy were examined. Methods Twenty-eight patients with repaired CHD (35 pregnancies, age: 26 ± 3.5 years at their first pregnancy, 22 ± 6.2 years post-repair) and 19 healthy pregnant volunteers (controls, 19 pregnancies, age: 28 ± 5.5 years) were enrolled. Holter monitoring and laboratory tests were examined at 28 ± 4 weeks of gestation and 22 ± 13 weeks postpartum in patients and 28 ± 3 weeks of gestation in controls. Time and frequency variables of HRV were analyzed. Results Compared with controls and postpartum, there was a significantly higher incidence of tachyarrhythmia during pregnancy in women with CHD (4 episodes of supraventricular tachyarrhythmia (SVT) and 5 of non-sustained ventricular tachycardia, P = 0.02). HR response in tetralogy of Fallot was impaired (781 ± 50 ms, P = 0.02). Most of HRV variables were significantly suppressed (average RR 740 ± 64 ms, SDRR 99 ± 22 ms, low and high frequency domains (341 ± 165 ms 2 and 256 ± 181 ms 2)( P < 0.05). Reduced SDRR and high frequency domains were observed in patients with tachyarrhythmia. Furthermore, there were increased left ventricular end-diastolic dimensions 48 ± 5 mm ( P = 0.001) and atrial natriuretic peptide levels 33 ± 13 pg/ml ( P = 0.01) in the CHD patients compared with postpartum levels. Conclusions Impaired autonomic nervous activity, volume overload of the heart and operative scar all play a contributory role in higher incidence of tachyarrhythmia during pregnancy in patients with repaired CHD compared to healthy pregnant controls. Close monitoring of patients with CHD for tachyarrhythmia during pregnancy is, thus, warranted.

Female Predominance and Transmission Distortion in the Long-QT Syndrome

Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons.

Diagnosis and Treatment of Arrhythmias in Women

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Is Gender a Risk Factor for Adverse Drug Reactions?

Drug-induced torsade de pointes is a rare life-threatening adverse drug reaction (ADR) which is strongly influenced by gender. Drugs that prolong cardiac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I(Kr)) of the delayed rectifier potassium current (I(K)). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electrocardiographic signs are subdued, the underlying blockade of I(Kr) current may precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity may result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisation) is associated with the occurrence of torsade de pointes and related ventricular arrhythmias. The QT interval is influenced by heart rate, autonomic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender differences impairing women's health. Clinical and experimental studies show that female gender is associated with a longer corrected QT interval at baseline and a greater response to drugs that block I(Kr), both of which facilitate the emergence of arrhythmia. This results most likely from a specific regulation of ionic channel expression (potassium, calcium, etc) by sex steroids, even though nongenomic effects may play a role as well. Estrogens facilitate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT response to drugs. Hence, underlying genetic defects of potassium channels that may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks I(Kr) and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced cardiac 'repolarisation reserve'. This is an important aspect of I(Kr) blockade to be aware of during the development of new drugs.

Cycling of inducibility of paroxysmal supraventricular tachycardia in women and its implications for timing of electrophysiologic procedures

Arrhythmias in women may be affected by phases of the menstrual cycle. This study was designed to determine the prevalence of perimenstrual clustering of spontaneous episodes of paroxysmal supraventricular tachycardia (SVT) in women. It also tested the hypothesis that women with this temporal pattern of events have an altered probability of induction of paroxysmal SVT during electrophysiologic testing at higher estrogen states (midcycle or with estrogen replacement therapy) than at low estrogen states (perimenstrual or without estrogen replacement). A structured history of the relation of spontaneous paroxysmal SVTs to phases of the menstrual cycle was obtained prospectively among 42 women referred during a 3-year period. Patients with cyclical patterns of spontaneous tachycardias, who had had negative electrophysiologic studies at midcycle or while receiving estrogen replacement therapy, had repeat procedures (1) when premenstrual or at the onset of menses, or (2) after stopping estrogen replacement therapy. Seventeen of 42 consecutive female patients (40%) had histories of perimenstrual clustering of arrhythmias. Six women (4 with normal menstrual cycles, 2 on estrogen replacement therapy), who qualified for paired electrophysiologic studies because of a negative initial electrophysiologic study that included provocation with isoproterenol, had inducibility into SVTs during the second study. All 6 had dual atrioventricular (AV) nodal pathway physiology, 4 had AV nodal reentrant tachycardia (AVNRT) induced, 1 had both AVNRT and reciprocating AV tachycardias, and 1 had nonsustained AVNRT and an atrial tachycardia induced. Successful ablation procedures were performed in 5 of the 6 patients. Thus, among women with a history of perimenstrual clustering of paroxysmal SVT and among those receiving estrogen replacement therapy, scheduling of elective electrophysiologic procedures at times of low estrogen levels (premenstrual or off estrogen replacement therapy) may facilitate the probability of a successful procedure.

Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence.

One of the most pronounced gender-based differences in response to drugs is women's far greater risk of developing the life-threatening ventricular arrhythmia called torsades de pointes (TdP). A review of the literature and databases of the Food and Drug Administration reveals that a much higher percentage of women than men develop TdP arrhythmias after taking a variety of drugs, such as antihistamines (terfenadine, astemizole), antibiotics (erythromycin), antimalarials (halofantrine), antiarrhythmics (quinidine, d-sotalol), and miscellaneous other drugs. All of these drugs have in common the ability to block potassium currents, thereby prolonging cardiac repolarization and the QT interval on the ECG. The available experimental data support the hypothesis that gender differences in specific cardiac ion current densities are responsible, at least in part, for the greater susceptibility of females for developing TdP arrhythmias. In isolated perfused rabbit hearts (Langendorff technique), female rabbit hearts display greater baseline and drug-induced (quinidine and d-sotalol) changes in QT intervals than male hearts, and at least two different repolarizing potassium current densities (IKr and IKl) are found to be significantly lower in ventricular cardiomyocytes from female rabbits compared with those from males. Thus, it appears that as in humans, clear gender differences exist in the electrophysiologic characteristics governing cardiac repolarization in rabbits. This model and perhaps others should be examined as predictors of functional and pharmacologic differences between men and women. Understanding the potential mechanisms responsible for the greater risk of drug-induced arrhythmias in women could lead to screening methods for identification of individuals at risk for drug-induced arrhythmias or to the development of drugs with reduced risk of inducing arrhythmia.

Termination of supraventricular tachycardia with intravenous adenosine in a pregnant woman with Wolff-Parkinson-White syndrome

Pregnancy is associated with an increased frequency of arrhythmias in women with Wolff-Parkinson-White syndrome. We describe the use of intravenous (IV) adenosine for the acute termination of a narrow complex tachycardia in a pregnant patient with this syndrome.A 26-year-old woman with known Wolff-Parkinson-White syndrome presented with dizziness, palpitations, and a narrow complex supraventricular tachycardia. We used IV adenosine to convert the arrhythmia to a normal sinus rhythm. During labor, the patient again developed a narrow complex supraventricular tachycardia, and fetal monitoring revealed recurrent deep variable decelerations. Intravenous adenosine resulted in conversion to sinus rhythm and restoration of the fetal heart rate to normal. Cesarean delivery produced a healthy male infant.Adenosine is effective in rapidly terminating maternal narrow complex tachyarrhythmias before and during delivery in women with Wolff-Parkinson-White syndrome. It can also treat fetal bradycardia resulting from the maternal arrhythmia.

Risk of ventricular arrhythmias in left ventricular hypertrophy: The Framingham Heart Study

The association of ventricular arrhythmias with left ventricular (LV) hypertrophy was examined in 6,218 participants in the Framingham Heart Study. Electrocardiographic (ECG) LV hypertrophy was present in 171 subjects and echocardiographic hypertrophy was detected in 869. Echocardiographic LV hypertrophy was associated with increased risk for each of 6 ventricular arrhythmia grades in men (relative risk up to 8.9, p < 0.01), and 4 of 6 grades in women (p < 0.05). Similarly, men with ECG LV hypertrophy were at increased risk for 4 of 6 arrhythmia grades (p < 0.05). However, owing to low prevalence ECG LV hypertrophy was not associated with arrhythmia in women. After adjustment for age, sex, systolic blood pressure, valvular heart disease, angina pectoris and acute myocardial infarction, the association of echocardiographic but not ECG LV hypertrophy with ventricular arrhythmia remained significant (p < 0.001). Thus, echocardiographic LV hypertrophy is more prevalent and more sensitive for ventricular arrhythmias than ECG LV hypertrophy.

Calcium Channel Blockers: An Intraoperative and Postoperative Trial in Women

This study analyzes the effects of intraoperative and postoperative calcium channel blockers on myocardial protection, postoperative arrhythmias, perioperative infarctions, and survival. Thirty-nine women undergoing consecutive coronary artery bypass operations were placed either in a control group (N = 23), in which standard cold potassium cardioplegia was used, or in a verapamil-nifedipine group (N = 16), in which verapamil (1 mg per liter) was added to the standard cardioplegic solution and nifedipine was instituted postoperatively. The verapamil-nifedipine group showed a significant reduction in postoperative levels of creatine phosphokinase ( p < 0.05). Levels of aspartate aminotransferase were also reduced (74 IU/L) compared with those for the control group (114 IU/L). In the control group, there were 3 early deaths secondary to abrupt ventricular fibrillation, but no patient in the verapamil-nifedipine group died or had serious early ventricular arrhythmias. Late hemodynamic variables were similar in both groups. We conclude that calcium channel blockers enhance myocardial protection during ischemic arrest and may diminish the incidence of fatal early postoperative ventricular arrhythmias in women undergoing coronary revascularization.